Part of what makes human immunodeficiency virus (HIV) so difficult to treat is its ability to elude the body’s immune system in a variety of ways. However, a recent study has described genetically-altered antibodies which have 100 times the HIV-fighting power of natural antibodies. This could be used to develop new treatments. Rachel Galimidi of Caltech was lead author of the paper, which was published in Cell.
Many viruses have hundreds of protein ‘spikes’ on their surface that Y-shaped antibodies are able to grab with both ‘arms’ in order to attack it. HIV, however, only has about 20 spikes which are sparsely arranged on the surface. If the antibody latches on with one arm, it has a difficult time finding another one within reach. Not only is the antibody unable to function properly and attack the virus without a firm grasp, but the decreased efficacy also makes it easier for the virus to evolve and negate the antibody’s efforts entirely. These factors might be contributing to HIV’s virulence. Galimidi’s team circumvented this obstacle by genetically engineering antibodies that allow both arms to latch onto a single spike.
"I think that our work sheds light on the potential therapeutic strategies that biotech companies should be using—and that we will be using—in order to make a better antibody reagent to combat HIV," Galimidi said in a press release. "A lot of companies discount antibody reagents because of the virus's ability to evade antibody pressure, focusing instead on small molecules as drug therapies. Our new reagents illustrate a way to get around that.”
Because HIV mutates so quickly, it is often difficult for antibodies to keep up. A select group of individuals with HIV create antibodies capable of attacking several forms of the virus, making them an ideal base for the genetic engineering.
The researchers took out the functional parts that bind viruses, called Fabs, and connected two of them to each end of spacer DNA strands. Rather than be restricted by the Y-shaped antibody, the end product looked more like a nunchuck. The researchers used different variations of the two Fabs connected at each end; some trials used Fabs from the same antibody, and others used Fabs from two different antibodies, which broadened the range of viruses they would be effective against.
Using flexible DNA not only allowed the Fabs to fit onto a single spike, but because the base pairs are precisely spaced, the researchers were able to use it as a ruler and make exact measurements in the antibodies. Different lengths of DNA were used in order to find which length best suited the Fab complexes. They were also able to determine that the DNA did not contribute to the antibody’s actions. This was important because the DNA was replaced by protein chains in the final product.
Through a number of trials, the scientists were met with more failed antibodies than successful ones, though those that were effective were tremendously so. Some of the antibodies were 10 to 1,000 times more potent than their naturally-occurring counterparts. Moving forward, the team will test the antibodies in mice that have been altered to have HIV-sensitive immune cells.
"Based on the work that we have done, we now think we know how to make a really potent therapeutic that would not only work at relatively low concentrations but would also force the virus to mutate along pathways that would make it less fit and therefore more susceptible to elimination," added senior author Pamela Bjorkman. "If you were able to give this to someone who already had HIV, you might even be able to clear the infection.”